1. Field of the Invention
The present invention relates to a biocompatible polyester for use in medical devices such as surgical sutures, matrices of sustained release preparations and an internal split-plate in fracture cores, and a process for preparation of the biocompatible polyester.
More particularly, the invention relates to a biocompatible polyester which has improved hydrolyzability and contains an introduced saccharide bond to a polymer chain of the biocompatible polyester having recurring structural units consisting of a glycolic acid unit and/or a lactic acid unit.
2. Description of the Related Art
Biocompatible polyester of the present invention has recurring structural units consisting of a glycolic acid unit and/or a lactic acid unit, and is a polymer having the recurring structural units represented by the formula (I): ##STR1## wherein R.sub.1 and R.sub.2 are a hydrogen atom or a methyl group, and may be the same or different.
The biocompatible polyester having the above recurring structural units is generally divided, in the above formula (I), into a glycolic-acid based polymer wherein a 80 to 100% portion of R.sub.1 and R.sub.2 is a hydrogen atom and a 0 to 20% portion is a methyl group, and a lactic-acid based polymer wherein a 0 to 80% portion of R.sub.1 and R.sub.2 is a hydrogen atom and a 20 to 100% portion is a methyl group.
Any of the above biocompatible polyester is nonenzymatically hydrolyzed in vivo into glycolic acid and lactic acid. These acids are finally converted to carbon dioxide and water through a metabolic pathway and are excreted from the organism. Hence, the above polyester is an interesting bioabsorbable material.
However, the glycolic-acid based polymer (hereinafter abbreviated as PGA) generally has poor solubility in various solvents, a high melting point of 180.degree. to 240.degree. C. and difficulty in molding. According to these properties, high molecular weight PGA is processed into fibers and used for sterile materials for surgery such as sutures and gauze.
Practically, surgical sutures prepared from the glycolic acid based polymer have already been marketed from ACC Co. Ltd. and Ethicon Co. Ltd. under the trade marks of Dexon (100% by mole of glycolic acid structure) and Vicryl (from 85 to 90% by mole of glycolic acid structure and from 10 to 15% by mole of lactic acid structure), respectively.
The glycolic-acid based polymer requires a long period, e.g. about a month until the polymer loses most of its initial strength by hydrolysis in vivo.
Consequently, it is desired to develop materials which can be hydrolyzed and absorbed within a much shorter period depending upon the portion and method of suturing.
On the other hand, the lactic-acid based polymer is usually divided into the following classes according to the proportion of lactic acid structure and glycolic acid structure.
That is, the classes are polylactic acid (hereinafter abbreviated as PLA) wherein a 100% portion of R.sub.1 and R.sub.2 in the formula (I) is a methyl group, and a lactic acid-glycolic acid copolymer (hereinafter abbreviated as PGLA) wherein a 0 to 80% portion of R.sub.1 and R.sub.2 is a hydrogen atom and a 20 to 100% portion of R.sub.1 and R.sub.2 is a methyl group excluding the situation where a 100% portion of R.sub.1 and R.sub.2 is a methyl group.
PLA can provide a high-strength polymer. A high molecular eight PLA, in particular, is processed into bars and plates and used for bioabsorbable plates of internal splints for fracture care.
On the other hand, PGLA is somewhat inferior in strength as a polymer and hence is used primarily for the matrix of sustained release preparations.
As mentioned above, the lactic-acid based polymer is excellent in processability and solubility in various solvents. Thus the polymer is processed into pellets, needles, films and microspheres, and is widely used for the matrix of sustained release preparations which are applied to internal imbedding and intravenous injection.
The bioabsorbable plates of internal splints for fracture care prepared from PLA requires from 6 to 12 months for hydrolysis in vivo. With the recent progress of medicine, it has been desired to develop materials which can be hydrolyzed within a much shorter period.
As to the PGLA matrix for sustained release preparations, it is also required to develop matrix materials which can be hydrolyzed within a much shorter period such as several days depending upon the kind and administration of drugs to be released.
As mentioned above, the biocompatible polyester is different in the object and mode of use depending upon its kind. However, a common subject for any kind of the biocompatible polyester is to develop materials having a higher hydrolyzability in vivo or materials controlled so as to obtain a desired level of hydrolyzability.
Thus, the development of such biocompatible polyester is now strongly demanded.
Accordingly, the following processes have been proposed for the preparation of glycolic-acid based polymer.
(1) Japanese Patent Publication SHO 62-31736(1987) discloses a preparation process for polyglycolic acid comprising polymerizing glycolide at a temperature of 160.degree. to 180.degree. C. in the presence of stannous octoate in an amount of 0.01 to 0.05% by weight per weight of glycolide and a monohydric alcohol having a saturated aliphatic straight chain containing even numbers of 12 to 18 carbon atoms in an amount of 0.5 to 2.8 times by weight per weight of stannous octoate.
(2) Japanese Patent Laid-Open Publication SHO 63-17929(1988) discloses a preparation process for polyglycolic acid having an inherent viscosity of 0.85 to 1.1 dl/g comprising polymerizing glycolide at a temperature of 220.degree. to 250.degree. C. in the presence of stannous octoate in an amount of 0.001 to 0.005% by weight per weight of glycolide and a monohydric alcohol having an aliphatic straight chain containing 10 to 18 carbon atoms in an amount of 0.11 to 0.22% by mole per mole of glycolide.
On the other hand, the following processes have also been proposed on the preparation of lactic-acid based polymers. For example, Japanese Patent Laid-Open Publication SHO 62-64824(1987) discloses a low molecular weight heterogeneous lactic-acid/glycolic-acid copolymer containing from 25 to 100% by mole of lactic acid structure and from 0 to 75% by mole of glycolic acid structure and having an inherent viscosity of 4 dl/g or less in a 1 g/100 ml solution of chloroform or dioxane; and a preparation process for the copolymer. An example of the above-mentioned Japanese Patent Laid-Open Publication SHO 62-64824(1987) describes a process for conducting polymerization of lactide with glycolide at 160.degree. C. by using 0.2% by weight of stannous octoate as a catalyst in the presence of dl-lactic acid hydrate to obtain the desired copolymer.
As to the preparation method for the biocompatible polyester, methods for catalytically conducting ring-opening polymerization of glycolide or lactide which are respectively dehydrated cyclic dimers of glycolic acid and lactic acid have been disclosed as described above. A process for carrying out the polymerization in the co-existence of alcohols such as lauryl alcohol or hydroxy-acids such as glycolic acid as a promoter (chain extender) has been proposed as the most general process.
However, any of the known preparation processes above have never disclosed a technique for enhancing hydrolyzability in vivo Or a technique for preparing biocompatible polyester having desired hydrolyzability.
The means for merely controlling, accelerating in particular, the hydrolysis rate of the biocompatible polyester has been principally to increase the amount of the promoter for use in the polymerization. That is, it has been found that increase in the amount of the promoter decreases molecular weight of the polyester formed and hence increases the hydrolysis. This leads to a lower molecular weight and the accompanied problem of lowering physical properties. Thus this technique has not been a favorable process for wide use.